JP2018524364A - Compositions, methods and pharmaceutical compositions for liver treatment and liver health maintenance - Google Patents

Abstract

A mixture of plant extracts, the plant extract comprising at least one artemisia extract, at least one aloe gel powder and at least one sisandra extract for liver treatment and liver health maintenance Compositions and methods are disclosed. A mixture of plant extracts, wherein the plant extract is at least one Artemisia extract rich in at least one polymer or biopolymer, at least one Aloe gel powder rich in at least one chromone, and Disclosed are compositions and methods for liver treatment and liver health comprising at least one lignan and at least one sisandola extract rich in organic acids.

Description

  This US patent application is filed with US Provisional Patent Application No. 6219711, filed July 15, 2015, entitled “Compositions and Methods for Liver Health”, and “Compositions, US, filed July 12, 2016, entitled “Methods, and Medical Compositions for Treatment of and Maintaining the Health of the Liver”. Claims priority to Utility Application No. 1520875, which are common to the owners and are generally Which is incorporated by reference.

  The field of the present subject matter is compounds useful for liver health care and stereoisomers, pharmaceutically acceptable salts or nutraceutical acceptable salts, tautomers, glycosides and prodrugs of the disclosed compounds. Compositions comprising, compositions for improving and maintaining liver health and related methods.

The liver is an important organ that plays a central role in the metabolism and detoxification of various endogenous and exogenous harmful substances. It is believed that over 500 chemical reactions occur in the liver. Various xenobiotics and foreign chemicals are known to cause hepatotoxicity, but in particular, acetaminophen (n-acetyl-p-aminophenol or APAP) and carbon tetrachloride (CCl ₄ ) are similar. It is commonly used to develop animal models that have a mechanism of action and mimic human-type liver toxicity. Biomarker sites derived from serum or liver homogenates have been used to review and / or analyze liver health, and changes outside the normal range are considered signs of injury to the organ. Among these biomarkers, the most commonly used are ALT (alanine aminotransferase), AST (aspartate aminotransferase), MDA (malondialdehyde), GSH (glutathione), SOD (superoxide dismutase), c -Jun N-terminal kinase (JNK), GSH-Px (glutathione peroxidase), CAT (catalase) and TNF-alpha (tumor necrosis factor-α). Liver panels such as AST, ALT, total bilirubin, conjugated and unconjugated bilirubin, bile acids, total protein, albumin, globulin and alkaline phosphatase have been used as standard screening methods for liver health . While ALT and AST are recognized to be nonspecific for liver damage, ALT shows relative specificity for the liver. For example, AST has a liver (9000: 1) to muscle (5200: 1) origin ratio. In contrast, ALT has a liver (7600: 1) to muscle (750: 1) origin ratio. The half-lives of total AST and ALT are 17 ± 5 hours and 47 ± 10 hours, respectively. ALT is stable for 24 hours in whole blood for 3 days at room temperature, 3 weeks in a refrigerator. However, ALT deteriorates rapidly with repeated freezing and thawing. Serum ALT was used to screen the efficacy of plant extracts in our study.

  APAP is a very safe and effective analgesic at therapeutic doses and an antipyretic. APAP is the most common cause of acute liver failure in the United States. APAP-induced hepatotoxicity is clinically relevant, well-studied, can be rapidly induced by a single dose in vivo, and evaluates the potential hepatoprotective effects of phytotherapy It is a conventional model.

  APAP-induced cell death is not caused by a single tragic event that stops the cell's survival function, but instead triggers a series of events that begin with the onset of reactive metabolite formation and mitochondrial dysfunction. Amplified by the JNK pathway, ultimately, loss of mitochondrial function and significant DNA degradation occurs, causing cell necrosis.

  The toxicity of APAP occurs through a very complex mechanism of action. As already established, the intracellular signaling mechanism of cell death induced by APAP is such that a small portion of the dose is cleaved from Cyp 2e1 and 1a2 (Zaher et al., 1998) by n-acetyl-p by the P450 enzyme. Initiated by being metabolized to benzoquinoneimine (NAPQI). Under normal conditions, this highly reactive metabolite is detoxified by GSH but causes extensive hepatic GSH depletion (Mitchell et al., 197), which is important when overdose. At the same time, increased amounts of NAPQI react with the sulfhydryl groups of the protein, causing covalent attachment of cellular proteins (Jollow et al., 1973). Interestingly, studies have shown that total protein binding in cells is not as important as adducts in mitochondria (Tirmenstein and Nelson, 1989; Qiu et al., 2001). Mitochondrial protein binding triggers mitochondrial oxidative stress (Jaeschke, 1990), which leads to the activity of apoptotic signal-regulated kinase 1 (Nakagawa et al., 2008) and c-Jun N-terminal kinase (JNK) (Hanawa et al., 2008) Mitochondrial oxidative stress amplification and peroxynitrite formation (Saito et al., 2010a) by mitochondrial JNK translocation. Extensive oxidative stress ultimately triggers the opening of the membrane permeability transition (MPT) pore in mitochondria with disruption of membrane potential (Kon et al., 2004; Masubuchi et al., 2005; Ramachandran et al., 2011a; Logicice and Boelsterli 2011), followed by the release of transmembrane proteins such as endonuclease G and apoptosis-inducing factor (AIF) from mitochondria (Kon et al., 2004; Bajt et al., 2008). Both endonuclease G and AIF translocate to the nucleus, causing DNA fragmentation (Cover et al., 2005; Bajt et al., 2006, 2011) and eventually cell death occurs. Collapse of mitochondrial membrane potential with ATP depletion and nuclear degradation is an important event leading to cell necrosis. Thus, there are multiple points of interference that can block these mechanisms when designing therapeutic interventions for liver protection.

  Knowing the time series of the model's pathological process provides guidance for therapeutic intervention. Oxidative stress and aseptic inflammation play an important role in APAP toxicity, but the model pathophysiology is metabolic activation between 0 and 2 hours after APAP toxicity, GSH depletion within the first 30 minutes. Characterized by a series of events including an intracellular mechanism of cell death between 2 and 12 hours, an inflammatory response in a 6 to 24 hour time frame, and a regeneration in a 24 to 72 hour time frame (Jaeschke et al. 2012a).

  As mentioned above, APAP overdose is characterized in humans by the formation of protein adducts (Davern et al., 2006; James et al., 2009), mitochondrial damage causing cell death and nuclear DNA fragmentation (McGill et al., 2012a). May cause severe liver toxicity. Therefore, it is desirable to utilize animal models that can share similar pathophysiological characteristics when testing plant extracts for liver protection. Thus, the mouse is the preferred model. This is because in in vivo experiments, the damage most closely resembles human pathophysiology in both mechanism and dose dependence. In fact, the main significant difference in APAP hepatotoxicity between mice and humans is that they show ALT peaks in humans 24 to 48 hours after exposure compared to mice where ALT peaks are present 6 to 12 hours after exposure. It has been suggested that humans have late toxicity (Larson, 2007). This difference can be explained in part as being due to the difference in absorption between the mouse and the two humans. In contrast, rats are common in natural product testing, but are poor models because most rat strains are almost insensitive to APAP toxicity (Mitchell et al., 1973; McGill et al., 2012b). ). Even at high doses of 1 g / kg and higher, APAP in most cases does not cause associated liver damage (Jaeschke et al., 2013). Also, although GSH depletion and protein adducts can be measured, there are fewer adducts in rat liver mitochondria compared to mice, initiating amplification events that cause sufficient mitochondrial dysfunction and subsequent necrotic cell death. Seems inadequate (McGill et al., 2012b). These basic differences between the two types of mice and rats have been reflected during the evaluation of phytotherapy. For example, in a rat study, a 3 g / kg APAP dose increased plasma ALT levels approximately 3-fold compared to baseline, and phytotherapy reduced this moderate liver injury by 33% (Ajith et al. 2007). Histological changes in this rat model were negligible and difficult to detect. On the other hand, in the mouse study, the increase in ALT after administration of 300 mg / kg APAP was more than 60 times the baseline, with a 75% reduction by phytotherapy (Wan et al., 2012). The histological changes caused by APAP toxicity and the protective effect of the drug were easily observed.

Halogenated alkane CCl ₄ , which has limited usage, is a well-known liver toxin and is widely used to induce acute toxic liver injury in a wide range of laboratory animals. People are exposed to CCl ₄ from the work environment and environmental pollution such as contaminated drinking water. Nevertheless, this chemical continues to play an important role as a model compound for elucidating the mechanism of action of hepatotoxic effects such as steatosis, fibrosis, hepatocyte death and carcinogenicity. (Slater 1981; Renner H. 1985; Reynolds 1963). This chemical is considered one of the chemically induced classical hepatotoxic animal models primarily related to free radical formation and lipid peroxidation.

Similar to APAP, CCl ₄ toxicity is initiated primarily by cytochrome P450s (Nelson and Harrison, 1987) such as (CYP) 2E1, CYP2B1 or CYP2B2, producing trichloromethyl free radicals (CCl ₃ −), which are reactive metabolites. However, this radical can initiate lipid peroxidation and ultimately cause overproduction of reactive oxygen species (ROS) and hepatocellular injury (Poyer et al., 1980; Albano et al., 1982). In the process, these radicals bind to cellular molecules (nucleic acids, proteins and lipids), interfere with important cellular processing processes such as lipid metabolism, and steatosis (liposis) and direct to these macromolecules. It can cause consequences such as mechanical damage (Weddle et al., 1976). These radicals may react with oxygen to form the highly reactive species trichloromethylperoxy radical CCl ₃ OO— (highly reactive species). Once produced, the lipidation oxidation chain reaction begins, attacking and destroying polyunsaturated fatty acids, particularly polyunsaturated fatty acids associated with phospholipids. This reaction affects the permeability of the mitochondria, endoplasmic reticulum and plasma membrane, resulting in loss of cellular calcium sequestration and homeostasis, which can contribute significantly to subsequent cell damage. In this regard, antioxidants and radical scavengers also protect hepatocytes from damage induced by CCl ₄ by disrupting the lipid peroxidation chain reaction and also study the mechanism of CCl ₄ toxicity. Have been used (Cheeseman et al., 1987). At the molecular level, CCl ₄ activates TNF-α (Czaja et al., 1995), nitric oxide (NO) (Chamulitrat et al., 1994, 1995) and transforming growth factor (TGF) in cells (Luckey et al., 2001), a process appears that appears to direct cells primarily in the direction of destruction or fibrosis. These suggest that plant extracts with anti-inflammatory activity may have potential uses in liver protection. Acute administration of large amounts of CCl ₄ causes severe necrosis, but low dose chronic administration is frequently used to induce liver fibrosis.

Oxidative stress is a natural ability to counteract or neutralize the harmful effects of free radicals by generating free radicals and interacting with defense networks by various reducing and scavenging endogenous antioxidants. The balance of the In the absence of proper adaptation by the body's antioxidant defense system, the accumulation of reactive oxidative species results in the activation of stress-sensitive intracellular signaling pathways, which in turn promotes cell damage that causes necrosis will do. Damage caused by oxidative stress affects the entire body as a system, but if life-related organs such as the liver where primary detoxification is performed to remove and metabolize harmful toxins such as alcohol are involved, The effects are even more harmful. As a result, the liver is induced by alcohol because alcohol and its primary metabolite, acetaldehyde, generate reactive oxygen species (ROS) and hydroxyl radicals (OH) that alter the liver's antioxidant defense system. Susceptible to damage. The most common pathological conditions such as fatty liver, hepatitis, fibrosis and cirrhosis are observed in alcohol-related liver damage as a result of repeated exposure to alcohol. These results involve the oxidation of cellular lipids, proteins and DNA and have been demonstrated in several laboratory animals (Wu and Cederbaum, 2003). Here, the most frequently used animal models with clinical implications such as APAP were used to confirm findings using a classic CCl ₄ -induced hepatotoxicity model. Regardless of the chemicals used to induce hepatotoxicity, both the APAP model and the CCl ₄ model are reactive oxygen produced by excess intermediate metabolites that cause protein oxidation, lipid peroxidation and DNA damage. Shares important processes in species-induced oxidative stress.

  For this purpose, it is desirable to develop, manufacture and utilize compositions, pharmaceutical compositions and related methods designed to treat the liver and maintain liver health. Ideal compounds, pharmaceutical compositions and compositions are (1) treating or preventing damage to mammalian hepatocytes; (2) promoting liver health; (3) detoxification and oxidation in mammals. Preserving preventive liver enzymes; (4) increasing liver detoxification capacity in mammals; (5) treating or preventing liver disease in mammals; (6) modifying liver inflammation in mammals; (7) It would be sufficient to provide treatment that includes any one or more of improving liver regeneration function. Ideal compounds and compositions may be derived from at least one plant extract or may contain at least one plant extract, which is rich in certain components. May or may not be abundant. As part of this development, it would be ideal to utilize frequently used acceptable models to test the compounds and compositions under consideration. It would also be desirable to reliably design therapeutic interventions for liver health by blocking some points in the mechanism of liver degradation and studying these results.

  A mixture of plant extracts, the plant extract comprising at least one artemisia extract, at least one aloe gel powder and at least one sisandra extract for liver treatment and liver health maintenance Compositions and methods are disclosed.

  A mixture of plant extracts, wherein the plant extract is at least one Artemisia extract rich in at least one polymer or biopolymer, at least one Aloe gel powder rich in at least one chromone, and Disclosed are compositions and methods for liver treatment and liver health comprising at least one lignan and at least one sisandola extract rich in organic acids.

  Free radicals that maintain liver function in mammals, minimize hepatocyte damage, promote healthy liver, protect liver's antioxidant integrity, neutralize toxins and affect liver health Reduce the effects of oxygen, trap reactive oxygen species, reduce oxidative stress, prevent the production of toxic metabolites, improve liver detoxification ability and / or function, wash liver, restore liver structure Protects hepatocytes from toxins in the liver, helps the liver blood flow and circulation, assists liver function, strengthens the liver, sedates, calms the liver, normalizes, relieves liver pain, is harmful Expelling chemicals and organisms, assisting in the metabolic processes of the liver, relieving liver discomfort, relieving fatty liver, improving liver detoxification, reducing liver enzymes, and adding natural oxidants Give, increase SOD, increase GSH, Reduce peroxidation, maintain fatty acid accumulation, maintain a healthy anti-inflammatory process, improve liver immune function, promote hepatocyte regeneration, improve liver regeneration function, stimulate bile release Also disclosed are pharmaceutical compositions and methods for promoting healthy bile flow, rejuvenating the liver, etc., wherein the pharmaceutical composition contains the composition under consideration as an active ingredient.

Shown is an HPLC chromatogram of Artemisia capillaris 70% ethanol extract.

  Briefly, the present disclosure relates to liver health care, including stereoisomers, pharmaceutically acceptable salts or dietary acceptable salts, tautomers, glycosides and prodrugs of the disclosed compounds. Useful compounds and compositions and related methods for improving liver health.

  The compounds and compositions under consideration are derived from or contain at least one plant extract, which may be rich in certain components, or It does not have to be abundant. As part of this development, a frequently used acceptable model was utilized to test the compounds and compositions under consideration. In addition, therapeutic interventions for liver health were designed by blocking several points in the mechanism of liver degradation and studying these results. The compounds, pharmaceutical compositions and compositions under consideration are (1) treating or preventing damage to hepatocytes in mammals; (2) promoting liver health; (3) detoxification and oxidation in mammals. Preserving preventive liver enzymes; (4) increasing liver detoxification capacity in mammals; (5) treating or preventing liver disease in mammals; (6) modifying liver inflammation in mammals; (7) It is sufficient to perform treatment including any one or more of improving liver regeneration function.

  Specifically, it comprises a mixture of plant extracts, the plant extract comprising at least one Artemisia extract, at least one Aloe gel powder and at least one Sisandra extract, for treating liver and liver. Disclosed are compositions, compounds and methods for maintaining health.

  In addition, a mixture of plant extracts, wherein the plant extract is at least one Artemisia extract rich in at least one polymer or biopolymer, at least one rich in at least one chromone Compositions, compounds and methods for liver treatment and liver health comprising at least one lignan and at least one sisandola extract rich in organic acids are disclosed.

  Free radicals that maintain liver function in mammals, minimize hepatocyte damage, promote healthy liver, protect liver's antioxidant integrity, neutralize toxins and affect liver health Reduce the effects of oxygen, trap reactive oxygen species, reduce oxidative stress, prevent the production of toxic metabolites, improve liver detoxification ability and / or function, wash liver, restore liver structure Protects hepatocytes from toxins in the liver, helps the liver blood flow and circulation, assists liver function, strengthens the liver, sedates, calms the liver, normalizes, relieves liver pain, is harmful Expelling chemicals and organisms, assisting in the metabolic processes of the liver, relieving liver discomfort, relieving fatty liver, improving liver detoxification, reducing liver enzymes, and adding natural oxidants Give, increase SOD, increase GSH, Reduce peroxidation, maintain fatty acid accumulation, maintain a healthy anti-inflammatory process, improve liver immune function, promote hepatocyte regeneration, improve liver regeneration function, stimulate bile release Also disclosed are pharmaceutical compositions and methods for promoting healthy bile flow, rejuvenating the liver, etc., wherein the pharmaceutical composition contains the composition under consideration as an active ingredient.

The concept of discovering a unique blend of compounds and extracts with enhanced potency to protect the liver from repeated exposure to oxidative stress is mindful of alcohol-induced liver damage, general fatigue and extreme fatigue Developed to put on. Historically, some plants rich in phenolic compounds have been associated with antioxidant activity in biological systems that act as scavengers for singlet oxygen and free radicals and have been reported to be used in herbal medicines. ing. Combining such plant materials with known efficacy and safety data is considered beneficial for overall liver health. Thus, various plant extracts were screened using the APAP model and the CCl ₄ model. As a result, some plant extracts showed a decrease in serum ALT in only one model, but the lead criteria to consider was to show efficacy in both models.

  From a total of 38 plant materials tested, only Sisandra, Artemisia and N931 were materials that demonstrated their efficacy in both models. N931 is a composition comprising a unique combination of 1 to 4% aloesin and 96 to 99% 200: 1 Aloe vera fallen inner leaf powder polysaccharide. As disclosed herein, the composition under consideration generally comprises an artemisia extract rich in one or more biopolymers, an aloe gel powder rich in one or more chromones and one or more lignans. And a mixture of plant extracts derived from Sisandra extract rich in organic acids.

The degree of inhibition observed for these substances was not equal between models. For example, extracts from Shizandora is was shown a higher protection of the liver damage caused by APAP (up to 48.9% at a dose of 500 mg / kg), at the same dose, the extract, by CCl ₄ Only 22.8% inhibition was shown in the induced hepatotoxicity model. On the other hand, Artemisia extracts such as Artemisia capillaris showed a 48.0% reduction in serum ALT levels at a dose of 400 mg / kg in a hepatotoxicity model induced by CCl ₄ . In contrast, the inhibition observed in the APAP-induced liver injury model was only 24.0% at this dose level when compared to the vehicle control. Considering these strong individual performances observed in separate models for each plant, the idea of combining these plant extracts to obtain better results in both models was strengthened. N931 showed moderate hepatoprotective activity in both models. As disclosed above, numerous studies have demonstrated the antioxidant activity of Sisandra, Artemisia and N931 with varying degrees of hepatoprotective ability. However, these studies have not previously been combined in any particular ratio to obtain the compositions discussed and disclosed, including SAL, which is generally understood as a unique combination of Sisandra, Artemisia and N931. It was.

An interesting finding is that at a dose of 400 mg / kg, Sisandra was blended with Artemisia capillaris at a ratio of 4: 1, 2: 1, 1: 1, 1: 2, and 1: 4 compared to the vehicle control for injury. , 2 in APAP model: 1 (2 × Shizandora is Artemisia capillaris), 1 in CCl ₄ model: 2 (Artemisia capillaris twice the Shizandora) is only 48.0% of serum ALT levels, respectively, and 40.6% It was reduced. These are insufficient to show the expected efficacy in a single ratio in both models, suggesting that a third component is required to complete the composition . N931 was considered to be a component of N931 because it showed moderate inhibition in both models. Addition of N931 to these two lead blends showed similar magnitude in both models, ie 52.5% and 46.3% hepatoprotective activity in both models, respectively It was thought to be added value as a result of the third component of the compound. When testing the benefits of blending these three plant materials, an unexpected synergistic effect was observed from the combination of these three plant materials, with each component at a given ratio at a dose of 400 mg / kg. Exceeded the expected results based on the simple sum of the observed effects.

  In fact, none of the components showed hepatoprotective activity of the same magnitude as that shown for the compounds or compositions under consideration, including sisandola, artemisia and N931. In addition, data from the liver panel, including AST, ALT, bile acid, total protein, total bilirubin, bound bilirubin, albumin and total protein, show that the composition under study is a control animal treated with a vehicle with an injury. In comparison, it was shown to contain hepatoprotective activity. As data from liver homogenates, the compositions under consideration containing SAL also supplemented depleted liver glutathione in association with increased activity in liver superoxide dismutase. The unique ratio of 4S: 8A: 3L subjects showed hepatoprotective activity in several animal models, associated with modulation of several oxidative stress specific biomarkers.

  As disclosed herein, Artemisia extract and Sisandra extract can be blended in a weight ratio of 4: 1 to 1: 4. In some embodiments under consideration, the aloe gel powder can be further blended in a weight percentage of about 5% to about 50% with a mixture of Artemisia extract and Sisandra extract. In other contemplated embodiments, the mixture of Artemisia, Sisandra and Aloe leaf gel powder may be provided in a ratio of 8: 4: 3, respectively.

  Sisandra extract is the component or component under consideration that can be utilized as part of the target compound or composition. Sisandra extract is from Schiandra chinensis, Sisandra elongate, Sisandra glabra, Sisandra glaiscens, Sizandra henra S incarnate, Sisandra rancifolia, Sisandra neglecta, Sisandra nigra, Sisandra propinka (Schisandra propofa) nqua), Sisandra pubescens, Sisandra repunda, Sisandra rubriflora, Sisandra rubrifolais, Sizandra rubrifolais Shisandra sphaerandra, Sisandra sphenanthera, Sisandra tomentella, Sisandra tuberculata, sizandra It may be obtained from any suitable source, including Vestita (Schisandra vestita), Sisandra viridis, Sisandra wilsoniana, or combinations thereof.

  The Sisandra extract may be rich in one or more lignans and organic acids, as discussed herein. The lignans of interest to be isolated from the sisandora extract are sisandrin, deoxycyzandrin, gamma-schizandrin, pseudo-gamma-sizandrin (Pseudo-ganzandrin), Wuweizusu B), Wuweizu C (Wuweizusu C), Isosizandrin (Isoschizandrin), Pregomisin (Egozandrin), Zizandol A (Sizandrol) C, D, E (S histantherin A, B, C, D, E), rubuschisantherin, sisanhenol acetate, sisanhenol B, sisanhenol, F, trashin A, B, trashin A, E , G, H, J, N, O, R, S, T, U (Gomisin A, B, C, D, E, F, G, H, J, N, O, R, S, T, U, ), Epigomisin O, Angeloyl Gomosin H, O, Q, T (Angeloylgomisin) H, O, Q, T, Igroyylgomisin H, P, Angeloiisogosin O (Angeloisogosin O) misin O), benzoyl - Gomisin H, O, P, Q, (Benzoyl- gomisin H, O, P, Q,) benzoyl - Isogomishin (Benzoyl- isogomisin), or a combination thereof. Organic acids of interest that are isolated from the Sisandra extract include malic acid, citric acid, shikimic acid, or combinations thereof.

  Artemisia extract is the component or component under consideration that can be utilized as part of the target compound or composition. Artemisia extracts are available from Artemisia absinium, Artemisia abbottium L. et al. (Artemisia abratinum L.), Artemisia afra, Artemisia annua L, Artemisia aborescens, Artemisia aborescens , Artemisia deserti, Artemisia iwamogi, Artemisia ludoviciana, Artemisia bulgaris, Artemisia ulgaria Ndodika (Artemisia oelandica), Artemisia Purinshipusu-Pump (Artemisia princeps Pamp), Artemisia Sakuraumu (Artemisia sacrorum), Artemisia scoparia (Artemisia scoparia), Artemisia Suterariana (Artemisia stelleriana), Artemisia Furijida-Wirudo (Artemisia frigida Willd ), Artemisia anethoides Matf., Artemisia anthefolia Weber., Artemisia folie Nakai (Artem) sia faurier Nakai), Origanumu-vulgare (Origanum vulgare), including Shiponosutajia-Chinenshisu (Siphenostegia chinensis) or any combination thereof, may be obtained from any suitable source.

  Artemisia extract may be rich in one or more biopolymers, as discussed herein. Polymers and biopolymers of interest isolated from Artemisia extracts are extracted with any suitable solvent including water, methanol, ethanol, alcohol, water mixed solvents or combinations thereof. In contemplated embodiments, the Artemisia extract comprises from about 0.01% to about 99.9% biopolymer with an individual molecular weight or median molecular weight greater than about 500 g / mol. In contemplated embodiments, the Artemisia extract comprises from about 0.01% to about 99.9% biopolymer having an individual molecular weight or median molecular weight greater than about 750 g / mol. In contemplated embodiments, the Artemisia extract comprises from about 0.01% to about 99.9% biopolymer having an individual molecular weight or median molecular weight greater than about 1000 g / mol.

  Aloe gel powder is another ingredient or component to be considered, Aloe arborescens, Aloe barbadensis, Aloe cremonophila, Aloe ferrox. , Aloe saponaria, Aloe vera, Aloe vera van chinensis or combinations thereof may be provided by any suitable source.

  The aloe gel powder may be rich in one or more chromones, as discussed herein. The chromone considered includes or is selected from aloesin, aloesinol, alloresin A, alloresin B, alloresin C, allelesin D, allelesin E, or any combination thereof. In contemplated embodiments, the at least one chromone composition may comprise from about 0.01% to about 100% of one or more chromones. In some contemplated embodiments, the chromone composition comprises about 1% to about 4% aloesin, the composition is essentially free of anthroquinone, and the aloe gel is selected from Aloe barbadensis or Aloe vera And at least one chromone is isolated from Aloe vera or Aloe ferox, or any combination thereof.

  The compound, pharmaceutical composition and composition under consideration may contain, or additionally contain, or consist of at least one hepatoprotectant. In some embodiments, the at least one hepatoprotective agent is milk thistle, turmeric, curcula, bupleurum, licorice, salvia, morus, kenvenia. ), Agrimony, cudrania, lyceum, citrus, prunus, yellow mume, korea gim, dandelion, grape , Grape seed, rubus, camellia, green tea, krill oi ), Yeast, soy bean plant powder or extract; isolated and concentrated silymarins, flavonoids, phospholipids, thios, pycnogenol, gelatin, soy lecithin, pancreas Enzymes; natural or synthetic N-acetyl-cysteine, taurine, riboflavin, niacin, pyridoxine, folic acid, carotene, vitamin A, vitamin B2, B6, B16, vitamin C, vitamin E, glutathione, branched chain amino acid, selenium, copper , Zinc, manganese, coenzyme Q10, L-arginine, L-glutamine, phosphatidylcholine and / or combinations thereof, and / or combinations thereof.

  In vivo metabolites of the disclosed compounds are also contemplated herein. Such products may arise from, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound mainly due to enzymatic methods. Thus, a compound under consideration is a compound produced by a method comprising administering the compound or composition under consideration to a mammal for a period of time sufficient to produce its metabolite. Such products typically administer a radiolabeled compound of the present disclosure at a detectable dose to an animal such as a rat, mouse, guinea pig, dog, cat, pig, sheep, horse, monkey or human. , Left for a time sufficient for metabolism to occur, and then the conversion product is identified by isolation from urine, blood or other biological sample.

  As used herein, the phrases “stable compound” and “stable structure” are used interchangeably to withstand and formulate isolation from a reaction mixture to a useful degree of purity. Used to indicate compounds that are sufficiently robust to withstand effective therapeutic agents.

  As used herein, the term “mammal” refers to humans, domestic animals (eg, laboratory animals or domestic pets (eg, rats, mice, guinea pigs, cats, dogs, pigs, cows, sheep, goats). , Horses, rabbits, primates)), and non-domestic animals (eg, wild animals).

  As used herein, the terms “optional element” or “optionally” may be used interchangeably, resulting in the occurrence of an element, component, event, or situation described thereafter. Means that the element, component, event or situation occurs and the case where the element, component, event or situation does not occur. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted. In other words, this description includes both substituted aryl groups and non-substituted aryl groups.

  Whether the compound, pharmaceutical composition and composition under consideration comprise or additionally contain at least one pharmaceutically acceptable carrier, or a dietary supplement acceptable carrier, diluent or excipient Or may consist of these. As used herein, the phrase “pharmaceutically acceptable carrier or dietary acceptable carrier, diluent or excipient” is acceptable for use in humans or livestock. Any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, approved by the US Food and Drug Administration Contains dispersants, suspensions, stabilizers, isotonic agents, solvents, or emulsifiers.

  The compound, pharmaceutical composition and composition under consideration may contain at least one pharmaceutically acceptable salt or dietary acceptable salt, or may additionally contain, or You may consist of these. As used herein, the phrase “pharmaceutically acceptable salt or dietary acceptable salt” includes both acid and base addition salts.

  As used herein, the phrase “pharmaceutically acceptable or nutraceutical acceptable acid addition salt” retains the biological effectiveness and properties of the free base and biological Or otherwise undesired, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid , Benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 , 2-Disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucohept Acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandel Acid, methanesulfonic acid, mucinic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamo Use organic acids such as acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid It refers to the acid addition salt made.

  As used herein, the phrase “pharmaceutically acceptable or nutraceutical acceptable base addition salt” retains the biological effectiveness and properties of the free acid and biological Or a base addition salt that is not otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salt is an ammonium salt, sodium salt, potassium salt, calcium salt or magnesium salt. Salts derived from organic bases include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine , Triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, procaine, hydrabamine, choline, betaine, venetamine, benzathine, ethylenediamine, glucosamine, Contains methyl glucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin salts, etc. It is. Particularly useful organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline or caffeine.

  Many produce solvates of the compound under consideration by crystallization or include solvates of the compound under consideration. As used herein, the term “solvate” refers to an aggregate comprising one or more molecules of a compound, pharmaceutical composition or composition under consideration and one or more molecules of a solvent. Point to. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compound, pharmaceutical composition or composition under consideration is monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate etc. and the corresponding solvates. It may exist as a hydrate containing form. The compound, pharmaceutical composition or composition under consideration may be a true solvate, but in other cases the compound, pharmaceutical composition or composition under consideration simply holds water accidentally It may be a mixture of water and some accidentally added solvents.

  A “pharmaceutical composition” or “nutritional supplement composition” is used to deliver a compound under consideration, a pharmaceutical composition or composition and a biologically active compound to a mammal (eg, a human). Refers to formulation with an art accepted medium. For example, the pharmaceutical compound, pharmaceutical composition or composition under consideration is reviewed and approved as an independent composition or by a prescription, over-the-counter (OTC), botanical, herbal medicine, homeopathic medicine, or government agency. It may be formulated or used as a component of other forms of medical products. Exemplary dietary supplement compositions to be considered are as independent compositions or in foods, new foods, functional foods, beverages, bars, food flavors, food additives, medical foods, dietary supplements or herbal products It may be formulated or used as a nutritional or bioactive ingredient. Medium generally accepted in the art includes any pharmaceutically acceptable or dietary acceptable carrier, diluent or excipient.

  As used herein, the phrase “rich in” refers to the amount of one or more active compounds found in the weight of the plant material or other source prior to extraction or other preparation. Or refers to a plant extract or other preparation in which the amount or activity of one or more active compounds is at least about 2-fold to about 1000-fold compared to activity. In certain embodiments, the weight of the plant material or other source prior to extraction or other preparation may be dry weight, wet weight, or a combination thereof.

  As used herein, a “major active ingredient” or “major active element” is found in a plant extract or other preparation that allows at least one bioactivity, or plant extract. Or it refers to one or more active compounds of interest that are abundant in other preparations. In certain embodiments, the major active ingredient of an abundant extract will be one or more active compounds that are abundant in the extract. In general, one or more major active ingredients directly or directly account for the majority (ie, greater than 50%) of one or more measurable bioactivity or bioeffect compared to the other components of the extract. Would give indirectly. In certain embodiments, the primary active ingredient is a minor component by weight in the extract (eg, about 50%, 25%, 20%, 15%, 10% of the components included in the extract, 5%, or less than 1%) may still provide most of the desired biological activity. Any composition under consideration containing the main active ingredient may or may not contribute to the activity of the abundant composition as a pharmaceutical or dietary supplement, A small amount of active ingredient that does not contribute to the level may also be included, and in the absence of the main active ingredient, the small amount of active ingredient may not be effective.

  As used herein, the phrase “effective amount” or “therapeutically effective amount”, when administered to a mammal (eg, a human), (1) treats or prevents damage to a mammal's hepatocytes. (2) promoting liver health; (3) preserving detoxification and antioxidant liver enzymes in mammals; (4) increasing liver detoxification capacity in mammals; (5) feeding Treating or preventing liver disease in an animal; (6) modifying liver inflammation in a mammal; (7) performing a treatment comprising any one or more of improving liver regeneration function; Refers to the amount of the compound, pharmaceutical composition and composition under consideration sufficient. The amount of the compound, pharmaceutical composition or composition under consideration that constitutes a “therapeutically effective amount” is the compound, the condition being treated and its severity, the mode of administration, the duration of treatment, or the weight of the subject being treated. Depending on age and age, one skilled in the art can determine in light of his knowledge and this disclosure.

  A “supplement”, as used herein, improves, promotes, assists, increases, regulates, manages, a particular state, structure or function associated with a natural state or biological process. Refers to products, compounds and / or compositions that control, maintain, optimize, modify, reduce, inhibit or prevent (i.e., diagnose, treat, alleviate, cure, disease, Or not used to prevent.) In certain embodiments, the supplement is a nutritional supplement. For example, with respect to conditions related to liver health, dietary supplements maintain mammalian liver function, minimize hepatocyte damage, promote healthy liver, and protect the antioxidant integrity of the liver. Neutralize toxins, reduce the effects of free radicals that affect liver health, scavenge reactive oxygen species, reduce oxidative stress, prevent the production of toxic metabolites, the ability of the liver to detoxify and / or Improve function, wash liver, restore liver structure, protect hepatocytes from toxins in liver, help liver blood flow and circulation, assist liver function, strengthen liver, sedate, Calms and normalizes the liver, relieves liver pain, expels harmful chemicals and organisms, assists in the metabolic processes of the liver, relieves liver discomfort, relieves fatty liver, detoxifies the liver Improves ability and lowers liver enzymes Natural oxidants, increase SOD, increase GSH, reduce hepatocyte peroxidation, reduce fatty acid accumulation, maintain a healthy anti-inflammatory process, improve liver immune function Used to promote hepatocyte regeneration, improve liver regeneration function, stimulate bile release, promote healthy bile flow, rejuvenate liver, etc. In certain embodiments, the dietary supplement is a special category of diet, food or both, and is not a drug.

  The terms “treat” or “treatment” or “reduce” may be used interchangeably and include, or are suspected of having, the disease or condition of interest. Refers to either a therapeutic or prophylactic / preventive treatment of the disease or condition of interest in (i) in particular, although such mammals have been diagnosed as predisposed to that condition, Preventing a disease or condition from occurring in a mammal when not diagnosed as having the condition; (ii) inhibiting the disease or condition, ie preventing its onset; (iii) disease Or alleviating the condition, ie regressing the disease or condition; or (iv) from the disease or condition without addressing the underlying disease or condition Jill alleviating symptoms (e.g., relieve pain, reduce inflammation,. Decreasing the detoxification capacity) it.

  As used herein, the terms “disease” and “condition” may be used interchangeably or a particular disease state or condition may not have a known causative agent. (The etiology has not yet been elucidated.) Thus, it is not recognized as a disease, but is only recognized as an undesirable condition or syndrome, and a more or less specific set of symptoms has been identified by the physician. May be different. In certain embodiments, the compounds under consideration, pharmaceutical compositions, compositions and methods are used to treat, for example, hepatitis, alcoholic liver disease, cirrhosis or both.

  As used herein, “statistical significance” refers to a p-value calculated using the Student t test of 0.050 or less, and the particular event or result being measured is accidentally Indicates that it is unlikely that it occurred.

  The chemical nomenclature protocol and any structural diagrams used herein are described in I.C. using the ACD / Name Version 9.07 software program or the ChemDraw Ultra Version 11.0 software naming program (CambridgeSoft). U. P. A. C. A modified form of the nomenclature system, the compounds of the present disclosure are named herein as derivatives of the central core structure (eg, imidazopyridine structure). In the case of complex chemical names utilized herein, a substituent is named before the group to which it is attached. For example, cyclopropylethyl includes an ethyl skeleton with a cyclopropyl substituent.

  In certain embodiments, the compounds and compositions under consideration (eg, pharmaceuticals, dietary supplements) promote liver health, improve liver health, maintain liver health, treat liver health Or manage, assist liver health, assist normal and comfortable range of liver detox function, improve liver free radical excretion ability, harmful from chemicals, drugs, metabolites and biotoxins Reduces free radical damage, preserves enzymes that affect liver health, hepatitis B virus infection, alcohol intake, metabolic disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty Hepatitis (NASH), alcoholic liver disease, hepatic encephalopathy, liver fibroproliferative disease (liver fibrosis), hepatocyte injury during hypoxia / reoxygenation, or any combination thereof, or Administered in an amount sufficient to protect against liver damage caused by chronic oxidative stress due to any other relevant indication described in the specification, generally with an acceptable toxicity to the patient May be.

  In certain other embodiments, the compounds and compositions under consideration (eg, pharmaceuticals, dietary supplements) are viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, alcoholic liver disease, fatty liver disease, steatosis , Steatohepatitis, nonalcoholic fatty liver disease, drug-induced liver disease, cirrhosis, fibrosis, liver failure, drug-induced liver failure, metabolic syndrome, hepatocellular carcinoma, cholangiocarcinoma, primary biliary cirrhosis, capillary bile duct , Gilbert syndrome, jaundice, or other indications related to liver toxicity, or a combination thereof, generally sufficient to treat liver disorders or diseases, including those with acceptable toxicity to the patient May be administered in any amount.

  A compound, pharmaceutical composition or composition, or a pharmaceutically acceptable salt or dietary acceptable salt thereof, in pure form or in the state of a suitable pharmaceutical or nutritional supplement composition Administration may be done by any of the acceptable dosage forms of the drug that serve a similar application. Prepare the pharmaceutical or nutraceutical composition under consideration by combining the compound under consideration with a suitable pharmaceutically acceptable or nutraceutical acceptable carrier, diluent or excipient Can be formulated into preparations in solid, semi-solid, liquid or gaseous form, eg tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols May be. Typical routes for administering such pharmaceutical or dietary supplement compositions include oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal or intranasal.

  The term “parenteral” as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical composition or dietary supplement composition to be studied is formulated so that the active ingredient contained therein is bioavailable when or immediately after administration of the composition to the patient. In some embodiments, the compositions and compounds under consideration may be designed or formulated to be capable of sustained release after administration.

  In certain embodiments, the composition under consideration is administered to a subject or patient in the form of one or more dosage units, for example, a tablet may be a single dosage unit, The compound container may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 20th edition (Philadelphia College of Pharmacy and Science, 2000). In any event, the subject composition to be administered is a therapeutically effective amount of the subject compound, or pharmaceutically acceptable salt, in order to treat the disease or condition of interest, in accordance with the teachings of this disclosure. Or it may contain a salt that is acceptable as a dietary supplement.

  The pharmaceutical composition or dietary supplement composition under consideration may be in solid or liquid form. In one aspect, the composition is in the form of a tablet or powder, for example, since the carrier is in particulate form. The carrier can be a liquid and the composition is, for example, an oral syrup, injection or aerosol useful for administration by inhalation.

  When intended for oral administration, the pharmaceutical or nutraceutical composition is either in solid or liquid form and the semi-solid, semi-liquid, suspension and gel forms are either solid or liquid. Included within the forms contemplated herein.

  As a solid composition for oral administration, the pharmaceutical composition or dietary supplement composition can be formulated in the form of powders, granules, compressed tablets, pills, capsules, chewing gum, wafers, bars and the like. Such solid compositions typically comprise one or more inert diluents or edible carriers. In addition, binders such as carboxymethylcellulose, ethylcellulose, cyclodextrin, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrin, alginic acid, sodium alginate, Primojel®, corn starch, etc. Disintegrants; lubricants such as magnesium stearate or Sterotex®; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavors such as peppermint, methyl salicylate or orange flavor Agent; one or more of the colorants may be present.

  When the pharmaceutical or nutraceutical composition is in the form of a capsule, such as a gelatin capsule, it may contain a liquid carrier such as polyethylene glycol or oil in addition to the types of materials described above.

  The pharmaceutical composition or dietary supplement composition under consideration may be in the form of a liquid, for example, an elixir, syrup, gel, solution, emulsion or suspension. The liquid may be for oral administration or delivery by injection, as two examples. When intended for oral administration, useful compositions contain, in addition to the compounds of this invention, one or more of a sweetening agent, preservatives, dye / colorant and flavor enhancer. In compositions intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included. .

  The liquid pharmaceutical composition or dietary supplement composition under consideration may comprise one or more of the following adjuvants, regardless of whether they are in solution, suspension or other similar form: Sterile diluents such as water for injection, saline solutions such as saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono- or diglycerides which can serve as solvents or suspending media, polyethylene glycol, Glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; acetates, citrates or phosphates Such as buffer, sodium chloride or dextrose Tonicity adjusting agent, such as. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Saline is a generally useful adjuvant. An injectable pharmaceutical or dietary supplement composition is sterile.

  The liquid pharmaceutical composition or dietary supplement composition to be studied, intended for either parenteral or oral administration, is an amount of the compound, pharmaceutical composition or composition to be studied so that an appropriate dosage is obtained. Should contain.

  The pharmaceutical composition or dietary supplement composition under consideration may be intended for topical administration, in which case the carrier suitably comprises a solution, emulsion, cream, lotion, ointment, or gel base. Also good. The base may contain one or more of diluents, emulsifiers and stabilizers such as, for example, petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, water and alcohol. The thickening agent may be present in a pharmaceutical composition or dietary supplement composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.

  The pharmaceutical composition or dietary supplement composition under consideration may be intended for rectal administration, eg in the form of a suppository, which melts in the rectum and releases the drug. Compositions for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include lanolin, cocoa butter and polyethylene glycol.

  The pharmaceutical composition or dietary supplement composition under consideration may contain various materials that modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The material forming the coating shell is typically inert and can be selected from, for example, sugar, shellac and other enteric coating agents. Alternatively, the active ingredient may be placed in a gelatin capsule.

  A pharmaceutical or nutraceutical composition in the solid or liquid form under consideration may comprise an agent that binds to the compound under consideration and thereby assists in the delivery of the compound. Suitable agents that can act in this capacity include monoclonal or polyclonal antibodies, proteins or liposomes.

  The pharmaceutical or nutraceutical composition in the solid or liquid form under consideration may include, for example, reducing the particle size to improve bioavailability. With or without excipients, the size of the powders, granules, particles, microspheres, etc. in the composition can be macro (eg, visible or at least 100 μm in size), micro (eg, from about 100 μm to about 100 μm). 100 nm size), nano (eg, may be 100 nm or less), any size between them or any of them to improve size and bulk density May be included.

  The pharmaceutical composition or nutritional supplement composition under consideration may comprise or consist of a dosage unit that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those with colloidal properties to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of the compounds of the present disclosure can be delivered in a single phase system, a two phase system, or a three phase system to deliver the active ingredient. Aerosol delivery includes the necessary containers, activators, valves, subcontainers, etc. that can be formed into a kit together. One of ordinary skill in the art can determine the most suitable aerosol without undue experimentation.

  The pharmaceutical composition or dietary supplement composition under consideration may be prepared by methodologies well known in the pharmaceutical or dietary supplement field. For example, a pharmaceutical or nutraceutical composition intended to be administered by injection can be prepared by combining the compound under consideration and sterile distilled water to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. A surfactant is a compound that interacts non-covalently with the compound under consideration to facilitate dissolution or uniform suspension of the compound in an aqueous delivery system.

  The compound, composition and pharmaceutical composition under consideration, or pharmaceutically acceptable or nutraceutical acceptable salt thereof, is administered in a therapeutically effective amount, and the therapeutically effective amount depends on the particular compound used. Activity; metabolic stability and length of action of the compound; patient age, weight, general health, sex and diet; mode of administration and time; excretion rate; drug combination; severity of a particular disorder or condition It will vary depending on a variety of factors, including the subject being treated.

  The compounds, compositions and pharmaceutical compositions under consideration, or their pharmaceutically acceptable or nutraceutical acceptable derivatives are also concomitant with the administration of one or more other therapeutic agents, prior to administration or It may be administered after administration. Such combination therapy involves administering a single pharmaceutical formulation or a dietary supplement formulation comprising the compound under consideration and one or more additional active agents, and each of the compound under consideration and each active agent, respectively. Administration in a separate pharmaceutical or nutraceutical formulation. For example, the compound under consideration and another active agent can be administered to a patient together in a single oral dosage composition such as a tablet or capsule, or each agent is administered in a separate oral dosage formulation. be able to. If separate dosage formulations are used, the compound under consideration and the one or more additional active agents may be administered at essentially the same time, ie simultaneously, or separately, in time differences, ie sequentially. Combination therapy is understood to include all these regimens.

  As used herein, it is understood that combinations of substituents or variables of the formulas shown are only allowed if such a contribution results in a stable compound.

  It will also be appreciated by those skilled in the art that in the methods described herein, the functional group of the intermediate compound may need to be protected with a suitable protecting group. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (eg, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include C (O) R ″ (R ″ is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups are known to those skilled in the art and can be added or removed according to standard techniques described herein. The use of protecting groups is described in Green, T .; W. And P.M. G. M.M. It is described in detail in Wutz, Protective Groups in Organic Synthesis (1999), 3rd edition, Wiley Edit, which is incorporated herein by reference in its entirety. As will be appreciated by those skilled in the art, the protecting group may be a polymer resin such as a Wang resin, a Rink resin or a 2-chlorotrityl chloride resin.

  Such protected derivatives of the compounds under consideration may not have pharmacological activity per se, but are administered to mammals and subsequently metabolized in the body to produce pharmacologically active compounds. Those skilled in the art will also understand that it may be formed. Such derivatives may therefore be described as “prodrugs”. All prodrugs of the compounds under consideration are included within the scope of this disclosure.

  Furthermore, the compound under consideration that exists in the form of the free base or free acid is pharmaceutically acceptable by treatment with a suitable inorganic or organic base or acid by methods known to those skilled in the art, Or it can be converted to a salt acceptable as a dietary supplement. The salt of the compound under consideration can be converted to its free base or acid form by standard techniques.

  In some embodiments, the compounds, compositions and / or pharmaceutical compositions under consideration can be isolated from plant sources, such as plants included anywhere in the examples and throughout the application. Plant parts suitable for isolating the extracts and compounds under consideration include leaves, bark, stem, stem bark, stem, stem bark, twig, tuber, root, root bark, bark surface (e.g. May include skin or bark, cork tissue, cork-forming layer, cork skin layer, or any combination thereof. , Heart skin (feet), flowers, or combinations thereof. The plant extracts considered include stems, stalks, stems, stem bark, twigs, tubers, roots, root barks, shoots, seeds, rhizomes, flowers and other reproductive organs, leaves, other aerial parts or combinations thereof Derived from at least one plant part selected from the group consisting of: In some related embodiments, the compound under consideration is isolated from a plant source and is synthetically modified to include any of the listed substituents. In this regard, synthetic modification of the compounds of interest isolated from plants can be accomplished using any number of techniques known in the art and within the knowledge of one of ordinary skill in the art.

Example 1: 7-8 week old purple bread mice with animal weights of 25-30 g were purchased from Charles River Laboratories (Wilmington, Mass.). One week after arrival, the animals were acclimatized to the environment and then weighed and randomly assigned to each group. ICR mice (5 / cage) were placed in a polypropylene cage and numbers were written on the tail to identify individuals. Each cage was covered with a wire bar lid and a filter top (Allentown, NJ). Each individual cage was identified with a cage card indicating the project number, test article, dose level, group and number of animals. A soft corn cob litter Harlan T7087 was used and changed at least twice a week. Animals were fed fresh water and rodent diet T2018 (Harlan Teklad, 370W, Kent, WA) ad libitum and placed in a constant temperature room (22.2 ° C) with a 12 hour light / dark cycle. All animal experiments were performed according to institutional guidelines consistent with laboratory animal care and use guidelines.

Example 2: A balanced treatment plan for an animal model of liver injury induced by acetaminophen (APAP) or carbon tetrachloride (CCL4) was developed and optimized to address prevention and intervention as follows. For the APAP-induced hepatotoxicity model, APAP (Lot No. MKBQ8028V, Sigma) at a dose of 400 mg / kg, warm saline (Lot No. 132908 from G-Biosciences, Lot No. 720729 from Quality Biologicals) (60 And was orally administered to ICR / CD-1 mice that had been dissolved in and fasted overnight to induce toxicity. For the CCl ₄ -induced hepatotoxicity model, CCl ₄ (Lot number SHBD5351V, Sigma) was dissolved in corn oil at a dose of 25 μg / kg and administered intraperitoneally to ICR / CD-1 mice fasted overnight to induce toxicity. I let you. For both models, the material was administered 48 hours, 24 hours, 2 hours, 6 hours after administration of APAP or CCl ₄ . In total, mice received 3 doses prior to chemical challenge and 1 dose after chemical challenge. 10% Tween-20 (Amresco Lot number 0134C141), 1% CMC (Spectra Lot number NH0454) or 1% MC (Lot number SLBK4357V) were used as carrier vehicles for all materials. Control mice that did not use APAP or CCl ₄ received carrier vehicle only. Serum ALT was measured with T24 (Phoenix Laboratories, Everett, WA).

Example 3: Preparation of plant extracts Plants were collected, prepared with different solvents based on the nature of their active compounds, and screened in a mouse hepatotoxic animal model. The 19 plants in Table 1 below, containing 16 different sites, showed serum ALT inhibition at different levels in either the mouse acetaminophen induced model or the CCl ₄ induced model. Only plants that have efficacy in both models are selected for further study.

  Milk thistle extract was produced as an 80% ethanol / 20% water extract of Sillybum marianum seeds with an extraction ratio of 40 to 50: 1. The ground seeds were extracted with 80% ethanol / 20% water and then the cake was separated from the supernatant by filtration. The solvent was removed under high vacuum to obtain a soft extract, which was mixed with maltodextrin and further dried with a spray dryer. Milk thistle extract was standardized to meet standards for total silymarin 50% or more and silibinin 30% or more. Silymarin is composed of a mixture of flavonolignans, silibinin, silidinin and silicristine. Silibinin is the main active ingredient of silymarin. Standardized extracts of milk thistle seeds are commercially available.

  As previously disclosed, N931 contains a unique combination of 1 to 4% aloesin and 96 to 99% 200: 1 Aloe vera endoderm gel powder polysaccharide blended by conventional methods. It is a composition. Aloe vera inner leaf gel powder polysaccharide was supplied by Aloecorp in the form of lyophilizate. The skin was manually removed from freshly washed leaves of the Aloe barbadensis plant and then the aloe juice was collected and treated with cellulase to inactivate the enzyme. During enzyme deactivation, the color was removed using activated carbon. The decolored filtrate was further transferred to a freeze-dried trap to obtain Aloe vera inner leaf gel powder, which was mixed with 1 to 4% aloesin to produce N931.

Example 4: Hepatoprotective activity of plant extracts against hepatotoxicity models induced by APAP and CCL4 Plant material obtained from ancient mining based on historical usage for liver protection and regeneration was converted to 70% ethanol And screened for efficacy in both APAP and CCl ₄ -induced hepatotoxicity. The material was orally administered to the animals at the doses specified in Tables 2-3. Most plant extracts showed inhibition of serum ALT in one model, but some plants showed efficacy in both models. Among these, Schizandra chinensis, Artemisia capillaris, milk thistle and loesin were selected for further study.

Example 5: Dose-response effects of selected plant extracts in the APAP model In the same way as described above, in the APAP-induced hepatotoxicity model, mug leaves (E1375), mugwort fruits (E1374) Sperm stalk (E1377), Artemisia capillaris (R0594) and Schizandra chinensis (2%) (L0498) were tested at doses of 100, 200, 300 mg / kg. 10% Tween 20 was used as the carrier vehicle for all materials. Control mice without APAP received only vehicle (10% Tween 20). Serum ALT was determined at T24. As shown in Table 4 below, two plant materials, such as Schizandra chinensis (2%) (L0498) and Artemisia capillaris (R0594), were 36.8% and 32.2% respectively at a dose of 300 mg / kg. Inhibition of serum ALT levels was demonstrated. These reductions were statistically significant. L0498 showed 100% survival at a dose of 300 mg / kg, while R0594 had 90% survival. At the lowest dose (100 mg / kg), L0498 showed only 30% survival. On the other hand, R0594 showed a 70% survival rate at this dose. Regardless of the dose, the survival rate for all the powders was as low as 40. These high mortality rates resulted in an uncertain rate of decrease in serum ALT levels. Thus, Schizandra chinensis (2%) (L0498) and Artemisia capillaris (R0594) had optimal potency at about 300 mg / kg and could be considered a true success in this model.

Example 6: Dose-response effects of selected plant extracts in the CCl ₄ model As described above, for the liver toxicity model induced by CCl ₄ , Agrimonia eupatoria (E1399) and loesin (QMA2) were administered at 400 mg / kg, 300 mg. Artemisia capillaris (R0594) and Schizandra chinensis (2%) (L0498) were tested at doses of 400 mg / kg and 300 mg / kg at doses of 200 mg / kg. 10% Tween-20 was used as the carrier vehicle for all materials. Control mice without CCl _{4 received} only vehicle (10% Tween-20). Serum ALT was determined at T24.

  As shown in Table 5 below, a dose-related decrease in serum ALT levels was mostly observed for all extracts. The greatest reduction in serum ALT levels was observed in mice treated with 400 mg / kg Artemisia capillaris (R0594) (48.0%) and then with 300 mg / kg of the same plant material (29.9%). It was. These reductions were statistically significant. At 400 mg / kg, both Agrimonia and Loesin showed very similar reductions in ALT levels (ie 28%) with P values of 0.07 and 0.04, respectively. Survival was 100% for all groups including vehicle-treated CCl4 controls. At least in this batch, Artemisia capillaris (R0594) showed superiority in inhibiting serum ALT levels over others tested.

Example 7: Preparation of Organic Extract of Artemisia Capillaris Dry, ground aerial portion (2.5 kg) of Artemisia Capillaris is cut and crushed, then about 15 times volume (37.5 L) of 70% ethyl alcohol Extracted with aqueous solution (v / v). Extraction was performed at 85 ° C. for 3 hours. After filtration, the ethanol solution was concentrated at 40 ° C. under high vacuum using a rotary evaporator. This extraction and concentration procedure was repeated twice for 2 hours with 10 volumes (25 L) of 70% aqueous ethyl alcohol (v / v). The concentrated extraction solution was evaporated to dryness in a high vacuum drying oven to obtain 480 g of Artemisia Capillaris 70% EtOH extract powder (Lot No. RN367-3-60M) with an extraction yield of 19.2%.

Dried and ground Artemisia Capillaris herb (180.4 g) was extracted 3 times with 70% aqueous ethanol by refluxing each for 1 hour. The organic solutions were combined and evaporated under high vacuum to give 37.7 g of 70% ethanol extract (R594-70EE) in 20.9% yield. Similar results were obtained using the same procedure, but replacing the organic solvent with methanol or ethanol, methanol extract (ME) or ethanol extract (EE), ethanol: H ₂ O (7: 3) extract, An ethanol: H ₂ O (1: 1) extract, an ethanol: H ₂ O (3: 7) extract and a water extract were obtained, respectively. The solvent extraction process is summarized in Table 6.

Example 8: Bioassay Induced Fractionation Method for Artemisia Capillaris Extract Artemisia capillaris 70% ethanol extract (RN425-7-70EE, 20 g) was partitioned three times in hexane (200 mL) and water (250 mL). The solvent was removed under high vacuum from the combined hexane solution to obtain 1.43 g of hexane extract (HE). The aqueous layer was extracted with ethyl acetate (200 mL) three times. The combined ethyl acetate layers were dried in vacuo to give 2.29 g of ethyl acetate extract (EA). The aqueous layer was further extracted three times with butanol (200 mL) to obtain 3.70 g of butanol extract (BU). The remaining aqueous layer was lyophilized to obtain 15.3 g of an aqueous extract (WA). 70% EE and HE, EA, BU and WA were tested in a hepatic toxicity model induced by CCl _{4 in} mice. HE, EA and BU were inactive, but 70% EE showed 25.27% ALT inhibition at 400 mg / kg, WA fraction was 37.49 at P ≦ 0.05 and 300 mg / kg level. % Inhibition.

  The active fraction WA was further fractionated by HP20SS chromatography. WA (4.4 g) was dissolved in 20% EtOH aqueous solution and loaded onto a single HP20SS (Diaion, Mitsubishi Chemical Corporation, Japan, 160 g) column that had been equilibrated through 20% EtOH aqueous solution. The column was eluted with 800 mL of 20% aqueous EtOH, 600 mL of 40% aqueous EtOH, 400 mL of 60% EtOH, 200 mL of 80% EtOH and finally washed with 200 mL of EtOH and 200 mL of acetone. Two major fractions HP-01 (3.67 g, 83.4%) and HP-02 (305.7 mg, 6.95%) were collected and tested in a hepatic toxicity mouse model induced by CCl4. The main components of HP-01 are oligosaccharides and polysaccharides. HP-02 contains mainly polyphenols. HP-01 showed similar ALT inhibition compared to WA, showing 32.86% inhibition at 300 mg / kg. HP-02 is inactive in the same model, indicating that polyphenols do not contribute to the activity of this plant.

The active fraction HP-01 was further fractionated with an LH-20 open column. HP-01 (1.06 g) was dissolved in water and loaded onto a single LH-20 column that had been equilibrated in advance with water, and four fractions LH were used using gradient elution with MeOH / H2O. -01 (43.4 mg, 4.26%), LH-02 (799.6 mg, 78.5%), chlorogenic acid (LH-03, 45.4 mg, 4.5%) and LH-04 (23. 1 mg, 2.27%). Due to sample limitations, only the main fraction LH-02 was tested in the in vivo test. LH-02 is 78.5% of HP-01 and did not show efficacy at the 300 mg / kg level in the animal model induced by CCl ₄ . Chlorogenic acid (C3878, Sigma-Aldrich, USA) is a component of HP-01, the ratio is about 4.5%, but did not show any inhibition when tested at the 200 mg / kg level. The in vivo data of this study clearly showed that water soluble components other than chlorogenic acid and polyphenols were responsible for the hepatoprotective activity of Artemisia extract. The content of active polysaccharide is less than 10% of the WA fraction. This information is summarized in Table 7.

Example 9: Fractionation separation of active HP-1 sample by membrane dialysis Liver protected fraction HP-01 from Example 8 and Table 7 from Artemisia capillaris is dissolved in an appropriate volume of distilled water and dissolved in distilled water On the other hand, the dialysis membrane tube was dialyzed 3 times for 3 hours each (cutoff MW2000). Both the retained dialysis solution and the combined dialysis solution were lyophilized to give two samples DA-1 (MW> 2000, 13.79%) and DA-2 (MW <2000, 84.54%). DA-2 was further dialyzed with a molecular weight cut-off 500 following the same procedure as above dialysis. DA-3 (500 <MW <2000, 16.7%) and DA-4 (MW <500, 79.7%) were collected. DA-1, DA-3 and DA-4 were tested in a mouse model induced by CCl4. DA-1 having a molecular weight greater than 2000 showed the highest inhibition in serum ALT levels with statistical significance compared to DA-3 and DA-4. Molecular weights less than 500 did not show efficacy in this in vivo model. This information is summarized in Table 8.

Example 10: HPLC analysis and quantification of Artemisia capillaris extract LCMS analysis of chlorogenic acid (1, C3878, Sigma-Aldrich, USA) and dicaffeoic acid (2-3) as marker compounds in Artemisia capillaris extract and It was identified based on literature reports and quantified using a Hitachi HPLC system C18 reverse phase column (Phenomenex, Luna C18, 10 μm, 250 mm × 4.6 mm) at a UV wavelength of 320 nm. The column was eluted with a binary gradient of 0.1% aqueous trifluoroacetic acid (TFA) and acetonitrile at a flow rate of 1 mL / min. Compounds 1 to 3 were quantified based on the reference compound chlorogenic acid. Chlorogenic acid content in Artemisia capillaris 70% EE collected from different sources varied from 1.5 to 4.8% (w / w) based on peak area calculations. This information is summarized in Tables 9-10.

Example 11: Determination of catechins in Artemisia Capillaris extract Catechins in the water fraction (WA) of Artemisia Capillaris extract were quantified by HPLC method. A Hitachi HPLC / PDA system equipped with a C18 reverse phase column (Phenomenex, USA, Luna 5um, 250mm x 4.6mm) was used for the detection and quantification of catechin at a flow rate of 1.0 mL / min, column temperature of 35 ° C, UV wavelength of 275 nm. Used for. Epicatechin (E1753, Sigma-Aldrich, USA) was not detected in all Artemisia samples, and very low content of catechin was detected and quantified based on the catechin standard (C1251, Sigma-Aldrich, USA). The catechin content in the WA fraction of Artemisia capillaris extract ranges from 0.02 to 0.32% and is independent of the hepatoprotective properties of Artemisia extract based on in vivo test results. This information is summarized in Tables 11-12.

Example 12: Separation of polysaccharides by membrane dialysis Untreated polysaccharide of HP-01 from Artemisia capillaris was dissolved in an appropriate volume of distilled water, and 3 times for 3 hours each in distilled water with distilled water. Dialyzed (cut-off MW2000). Both the retained dialysis solution and the combined dialysis solution were lyophilized to give two samples DA-1 (MW> 2000, 13.79%) and DA-2 (MW <2000, 84.54%). Both samples were tested in a mouse model induced by CCl _4.

Example 13: Analysis and quantification of polysaccharides by gel permeation chromatography The active fraction WA of Artemisia capillaris extract was also analyzed by gel permeation chromatography, a well-established method for assessing the molecular weight distribution of polysaccharides. . Artemisia capillaris polysaccharides were analyzed using a PolySep-SEC-P5000 column (Phenomenex, OOH-3145KO column, 300 mm × 7.8 mm) with a Hitachi HPLC system equipped with a refractive index detector. The mobile phase was 0.1M NaCl and was 25 minutes at a flow rate of 0.7 mL / min. For each sample, 20 μL was injected at a concentration of 10 mg / mL. Polysaccharides are quantified in 7 ranges divided into> 2000, 2000-1000, 100-500, 500-200, 200-50, 50-10, 10 kDa, based on 6 dextran molecular weight standards (American polymer Standards). did. The molecular weight distribution of the water fraction samples from different extracts varied. Liver protective activity is associated with a large molecular weight distribution. Although the total polysaccharide content is similar among Artemisia capillaris samples, the weight distribution is quite different. The higher the polysaccharide content, the better effect was observed for Artemisia capillaris. The molecular weight distribution is shown in Table 13.

Example 14: CCl ₄ Artemisia the model capillaris fraction hepatoprotective activity hexane (HE), ethyl acetate (EA), in order to evaluate the butanol (BU) and hepatoprotective activity of Artemisia capillaris fractions in water, CCl ₄ A hepatotoxicity model induced by is used. Control mice received only 10% Tween-20. Serum ALT was determined at T24. The Artemisia fraction was administered at a dose of 300 mg / kg, while the starting material was administered at a dose of 400 mg / kg.

  As seen in Table 14, the highest inhibition of serum ALT was observed in mice treated with Artemisia water fraction at a dose of 300 mg / kg, indicating that there is an activity marker in this fraction It shows the possibility. However, this does not exclude the presence of other active markers in other fractions. The original material (R684) maintained its potency at a dose of 400 mg / kg. In this model, the survival rate for all groups was 100%.

Example 15: Preparation of organic extract from Shisandra Chinansis fruit A total of 20 g of dried Shisandra chinansis fruit was placed in two 100 ml stainless steel tubes, using an ASE300 automatic extractor at 80 ° C, 1500 psi, 70% organic EtOH. Extracted twice with aqueous solution. The extraction solution was automatically filtered and collected. The combined solution was evaporated to dryness on a rotary evaporator to give a crude 70% EtOH extract (9.65 g, 49.5%).

Similar results were obtained using the same procedure, but replacing the organic solvent with methanol or ethanol, methanol extract (ME) or ethanol extract (EE), ethanol: H ₂ O (7: 3) extract, An ethanol: H ₂ O (1: 1) extract, an ethanol: H ₂ O (3: 7) extract and a water extract were obtained, respectively.

  Schisandra chinensis extract was produced by extracting dried fruits with 70% ethanol / 30% water (v / v). This extract was further processed to obtain an extract in a powder form (lot number) containing 2% or more of total sisandrin including sisandrin, sisantellin A, sisandrin A (deoxycisandrin) and sisandrin B.

Example 16: HPLC analysis and quantification of Schisandra Chinansis extract Sisandrin (Lot No. 110857, National Institute for Food and Control, China), Sisantellin A (Lot No. 11529-200503, National Institute for Food and Condo, China and Condo, China) (Deoxycisandrin, lot number 110764-200107, National Institute for Food and Control, China), Sisandrin B (lot number 110765-200508, National Institute for Food and Control, China), four kinds of active marker compounds Identified in ndra chinensis extract, Schisandra chinensis reference standard (lot number 140217, National Institute for Food and Control, China) was confirmed using.

  The active marker compounds were quantified by HPLC using a C18 reverse phase column (Phenomenex, Luna C18, 10 μm, 250 mm × 4.6 mm) of a Hitachi HPLC system using a UV wavelength of 250 nm by comparison with a reference standard. The column was eluted with water and acetonitrile at a flow rate of 1 mL / min. The gradient table for this example is shown in Table 15. After identifying and integrating the individual peaks, the total content of four compounds including sisandrin, sisanteline A, sisandrin A and sisandrin B was calculated based on RSM and the information is shown in Table 16.

Example 17: HPLC Quantification of Organic Acids in Sisandra Fruit Extracts The presence of malic acid, shikimic acid and citric acid in 70% EtOH extracts produced in-house from different collections was confirmed and listed in Table 17 Yes. The organic acid uses a Hypersil GOLD aQ column (4.6 × 250 mm, 5 μm), 50 mM potassium dihydrogen phosphate (pH adjusted to 2.8 with H ₃ PO ₄ ) as a mobile phase, and constant composition conditions The sample was quantitatively analyzed by HPLC at 5 ° C. for 20 minutes at a flow rate of 0.7 ml / min. Organic acids were detected using a 205 nm UV detector and identified based on retention time by comparison with organic acid standards.

Example 18: After selecting the read plants such as different combinations of Artemisia extract and Shisandora extract Artemisia Capillaries and Schisandra chinensis for liver protection in APAP model and CCl ₄ model, hepatotoxicity induced by APAP and CCl ₄ In the model, its efficacy in liver protection was evaluated at different combination ratios of 4: 1, 2: 1, 1: 1, 1: 2, and 1: 4. The combination of the two plants was encoded as “SA” using the first letter of each plant, ie “S” for Schisandra chinensis and “A” for Artemisia capillaries. As shown in Table 18 below, all blends showed some kind of hepatoprotection, but when measured at serum ALT levels, mice were mixed with a 2: 1 ratio of Sisandra and Artemisia in total volume. When treated at 400 mg / kg, a 48.0% reduction was observed, the highest statistically significant protection. Similarly, in the CCl ₄ model, the highest statistically significant liver when mice were treated with a 1: 2 blend of sisandola and artemisia at a total volume of 400 mg / kg as measured by serum ALT levels. A 40.6% reduction in protection was observed. In both models, survival at this particular ratio was 100%.

Example 19: Preparation of a combined SAL composition 320 g of Schisandra extract (Lot No. E1458), 263 g of Artemisia extract (Lot No. RN425-13), 377 g of Artemisia extract (Lot No. RN425-14) and 240 g of N931 (E1459 2% aloesin) was blended for 1 hour at 30 rpm using a Ribbon blender (Hankook PM EMG, Korea) to produce the SAL combination composition (lot number RN425-1501) to be studied. : Artemisia: N931 = 1: 8: 3 in a weight ratio of 1.17 kg of SAL combination (lot number RN425-1501) was obtained.

Example 20: Schisandra in APAP / CCl ₄ model Chinensis, for Artemisia capillaris and evaluation of hepatoprotective activity of the blend of N931 further hepatoprotective activity, by designated SAL by adding the third lead component (Roeshin) Two of the Schidra chinensis and Artemisia capillaries lead blend ratios at 2S: 1A (APAP model) and 1S: 2A (CCl ₄ model) were selected. “L” represents loesin. N931 was added in ratios of 20, 20 and 30% by weight for the 2S: 1A combination and in ratios of 10, 20 and 25% by weight for the 1S: 2A combination. This composition was tested in hepatotoxicity model induced by APAP / CCl _4. Mice were treated with the composition SAL at a dose of 400 mg / kg. As can be seen in Table 19, all compositions at different ratios showed some liver protection, but mice were treated with SAL at a ratio of 106.7 / 213.3 / 80, 400 mg / kg, respectively. When treated with dose, the greatest reduction in serum ALT (51.9%, P = 0.01) was observed, thus maximal protection. In this model, the survival rate was 100% at this particular ratio.

  Similarly, as seen in Table 19, all compositions at different ratios showed some liver protection, but mice were treated with SAL at 400 mg at a ratio of 106.7 / 213.3 / 80, respectively. When treated at a dose of / kg, the greatest reduction in serum ALT (42.3%, P = 0.01) was observed. In this model, the survival rate was 100% at this particular ratio.

  Multiple compositions have shown efficacy in protecting the liver, but in both models resulting in a final 4S: 8A: 3L ratio for composition SAL when 20 wt% loesin is added at a 1S: 2A ratio. The best protection was observed. As a result, this ratio of 4S: 8A: 3L was considered as the lead composition.

Example 21: Dose-response effect of a composition comprising Schisandra Chinansis, Artemisia Capillaris and N931 in a model of hepatotoxicity induced by APAP and CCl ₄ Optimal dose of composition SAL, which would result in significant liver protection, APAP and It was evaluated in both models induced by CCl _4. Mice were orally administered composition SAL at doses of 400 mg / kg, 325 mg / kg and 250 mg / kg suspended in 10% Tween-20. The vehicle control group received only the carrier solution. As seen in Table 20, in the APAP group, inhibition related to the dose of serum ALT was observed for the composition. 52.5% (p = 0.001), 48.5% (p = 0.012), and 34. For mice treated with 400 mg / kg, 325 mg / kg and 250 mg / kg doses of SAL, respectively. An inhibition of 6% (p = 0.079) was observed. Similarly, in the CCl ₄ group, inhibition related to the dose of serum ALT was observed for the composition. 46.3% (p = 0.003), 39.5% (p = 0.007) and 29.29 for mice treated with SAL at doses of 400 mg / kg, 325 mg / kg and 250 mg / kg, respectively. 9% (p = 0.036) inhibition was observed. In both models, the survival rate for all groups was 100%. Composition SAL gave statistically significant (CCL4) protection in liver injury at 1S: 2A with 20% L at dose levels as low as 250 mg / kg.

  Here, as seen at 4S: 8A: 3L at the highest dose tested (400 mg / kg), the efficacy of individual plants such as Sisandra, Artemisia and Loesin corresponds to the ratio of each plant in the sympathetic SAL Tested at a dose. As seen in Table 20, an average of 20% inhibition with 70-80% survival was observed for these plants at a given dose.

Example 22: Evaluation of Synergistic Effects of Composition SAL The Colby equation (Colby, 1967) was used to evaluate the benefits of combining Schidra chinensis, Artemisia capillaris and N931 in both APAP and CCL4 models. As can be seen from Table 21 below, the observed value is greater than the hypothetical value expected in both models (A + B-C), which indicates that the SAL is calculated by blending the three components in a specific ratio. It shows that there is a synergistic effect when getting. Shizandora advantage blending Artemisia and N931 was confirmed by synergistic protection of liver damage resulting from APAP and CCl _4.

Example 23: Using the hepatoprotective activity APAP and both hepatotoxicity model induced by CCl ₄ in SAL composition for the individual components at a dose of 300 mg / kg, liver protective activity against the individual components of the composition SAL Were compared using reduced serum ALT levels as a measure of efficacy at a dose of 300 mg / kg. 10% Tween-20 was used as the carrier vehicle for all materials. Control mice received only Tween-20. In addition to serum ALT, T. Protein, T. Liver panels such as bilirubin, albumin, AST and bile acids were measured at T24 for controls, APAP / CCl ₄ , SAL.

  As seen in AST as a measure of potency in Tables 23 and 24, the composition (SAL) showed enhanced liver damage protection over the vehicle (ie 60.6%) in the APAP model. In mice treated with SAL, S (Sisandra), A (Artemisia) and L (N931), statistically significant 47.1%, 42.2%, 42 of serum ALT compared to the vehicle group, respectively. Reductions of 0.0% and 16.6% were observed. The lowest survival rate (50%) was observed in mice treated with Artemisia.

Upon confirming the APAP model, composition SAL showed greater liver protection than each individual component at a dose of 300 mg / kg in the CCl ₄ model using serum ALT as a measure of efficacy. Furthermore, using AST as a measure of efficacy, the composition (SAL) showed higher damage protection than the vehicle (ie, 32.5%). In this model, the survival rate for all groups was 100%.

As shown in Table 24, composition SAL was compared to bile acid, T. cerevisiae in the APAP model compared to APAP positive mice treated with vehicle. Bilirubin and T.W. It showed improvement in liver related biomarkers such as protein. Similarly, statistically significant bile acid clearance was observed for mice treated with composition SAL in the CCl ₄ model when compared to the vehicle group.

Example 24: To demonstrate the superiority of hepatoprotective activity of APAP and potency confirmation test composition of Composition SAL in hepatotoxicity model induced by CCL4 SAL, both hepatotoxicity model induced by APAP and CCl ₄ A confirmation study was conducted using. Mice were orally administered at 400 mg / kg using composition SAL. 10% Tween-20 was used as the carrier vehicle for all materials. Control mice received only Tween-20. In addition to serum ALT, T. Liver panels such as protein, total bilirubin, direct and indirect bilirubin, albumin, globulin, AST, bile acid and ALP were measured at T24 for controls, APAP / CCl ₄ , SAL.

  As seen in Tables 25 and 26 below, statistically significant inhibition in serum ALT, AST, bound bilirubin and bile acids was observed for mice treated with composition SAL. These inhibitions were 34.0%, 44.5%, 60.0% and 26.7% reduction from the vehicle treated group. Similarly, composition SAL shows a marked statistically significant decrease (44.0% decrease) in serum ALT levels and a strong decrease trend in AST (35.9% decrease) compared to vehicle treated mice. It was. Overall, composition SAL provides greater protection against liver damage in multiple frequently used animal models, as shown in Table 27.

Example 25: Effect of Composition SAL on Oxidative Stress Biomarker in Liver Homogenate Taken from CCl ₄ Induced Liver Toxicity Model Composition SAL in Protecting Liver Using CCl ₄ Induced Liver Toxicity Model An additional confirmation assay was performed to assess the effect. Mice were orally administered at 400 mg / kg using composition SAL. 10% Tween 20 was used as the carrier vehicle. Control mice received only Tween 20. Liver tissue was collected immediately after necropsy and stored in dry ice until transferred to -80 ° C. The material was then placed in dry ice for final specimen processing and biomarker analysis to the contract laboratory (Brunwick Laboratories, 200 Turnpike Rd, MA 01772, USA). Liver glutathione (GSH) and superoxide dismutase (SOD) were evaluated.

  Glutathione (GSH) is an important intracellular tripeptide thiol that helps protect cells from free radical damage by providing a reducing agent that corresponds to the reduction of lipid hydroperoxides. During this step, oxidized glutathione (GSSG) is produced as a reaction product. GSH levels have been used as biomarkers that are indicative of oxidants and oxidative stress levels in cells and tissues in vivo. In this analysis, the sulfhydryl group of GSH reacts with DTNB (5,5'-dithio-bis-2-nitrobenzoic acid) to produce a yellow 5-thio-2-nitrobenzoic acid (TNB) product. . The amount of GSH in the biological sample is determined via measurement of the absorbance of TNB at 410 nm.

  Superoxide dismutase (SOD) is a metalloenzyme that catalyzes the disproportionation of superoxide anions to molecular oxygen and hydrogen peroxide. SOD is considered to be one of the most important antioxidant enzymes in vivo. The SOD assay is a colorimetric assay that utilizes tetrazolium salts and measures the disproportionation of superoxide radicals induced by xanthine oxidase and xanthine, and the activity of SOD in a given sample is determined using the SOD standard. Quantified by the generated standard curve. One unit of SOD is defined as the amount of enzyme required to exhibit 50% disproportionation of the superoxide radical.

  As seen in Table 28 below, when considered per gram protein level for each biomarker tested, composition SAL supplemented with depleted liver glutathione in association with increased liver superoxide dismutase. These findings, in conjunction with previously disclosed liver panel data, strongly suggest that composition SAL has hepatoprotective activity from oxidative stress caused by liver injury induced by CCL4.

Example 26: Evaluation of the hepatoprotective activity of a blend of Astragalus Membranous, Schisandra Chinansis and Artemisia Capillaris at specific ratios in a hepatic toxicity model induced by CCl ₄ Liver of a combination composed of two additional lead plant extracts Protective activity was also assessed in a hepatic toxicity model induced by CCl ₄ in mice. Astragalus membranous was combined with Schisandra chinensis or Artemisia capillaris in ratios of 1: 1, 1: 2, 2: 1, 1: 4 and 4: 1. As shown in Table 29, when Astragalus was blended with Sisandra, only one ratio (ie 1: 4) showed a statistically insignificant reduction in serum ALT compared to vehicle-treated injured mice. (34.1%). In contrast, greater hepatoprotection was observed when Astragalus and Artemisia were combined. Statistically significant 46.3% and 57.7% inhibition of serum ALT was observed for Astragalus: Artemisia ratios 2: 1 and 4: 1, respectively. For all ratios tested in this model, the survival rate was 100%.

  Accordingly, stereoisomers, pharmaceutically acceptable salts or nutraceutical acceptable salts, tautomers, glycosides and prodrugs of the disclosed compounds, as well as related methods for improving and maintaining liver health. Specific embodiments and methods of compounds and compositions useful for liver health care have been disclosed. However, it should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. Accordingly, the subject matter of the invention is not limited except as to the spirit of the disclosure herein. Moreover, in interpreting the specification and claims, all terms should be interpreted in the widest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be construed as referring to elements, components or steps in a non-exclusive manner, and the referenced elements, components or elements It indicates that a process may be present or utilized or may be combined with other elements, components or processes not explicitly mentioned.

Claims (38)

  A mixture of plant extracts, the plant extract comprising at least one artemisia extract, at least one aloe gel powder and at least one sisandra extract for liver treatment and liver health maintenance Composition.   Of plant extracts derived from Artemisia extract rich in at least one polymer or biopolymer, Aloe gel powder rich in at least one chromone and Sisandra extract rich in at least one lignan and organic acid A composition for treating the liver and maintaining the health of the liver, comprising a mixture.   The composition of claim 1, wherein the Artemisia extract and the Sisandra extract are blended in a weight ratio of 4: 1 to 1: 4.   2. The composition of claim 1, wherein the aloe gel powder is further blended with a mixture of Artemisia extract and Sisandra extract in a weight percentage of about 5% to about 50%.   The composition of claim 1 wherein the mixture of Artemisia, Sisandra and Aloe leaf gel powder is in a ratio of 8: 4: 3.   The composition of claim 2, wherein the Artemisia extract comprises 0.01% to 99.9% biopolymer having a molecular weight greater than 500.   Artemisia extracts are available from Artemisia absinium, Artemisia abbottium L. et al. (Artemisia abrotherum L.), Artemisia afra, Artemisia annua L, Artemisia artheis, Artemisia artheis, and Artemisia deserti, Artemisia iwamomogi, Artemisia ludoviciana, Artemisia bulgaris, Artemisia ulgarte Randodika (Artemisia oelandica), Artemisia Purinshipusu-Pump (Artemisia princeps Pamp), Artemisia Sakuraumu (Artemisia sacrorum), Artemisia scoparia (Artemisia scoparia), Artemisia Suterariana (Artemisia stelleriana), Artemisia Furijida-Wirudo (Artemisia frigida Willd ), Artemisia anethoides Matf., Artemisia anthefolia Weber., Artemisia Foley Nakai (Artem) 2. The composition of claim 1 comprising isia faurier Nakai, origanum vulgare, siphenostia chinensis, or any combination thereof.   Artemisia extracts are available from Artemisia absinium, Artemisia abbottium L. et al. (Artemisia abrotherum L.), Artemisia afra, Artemisia annua L, Artemisia artheis, Artemisia artheis, and Artemisia deserti, Artemisia iwamomogi, Artemisia ludoviciana, Artemisia bulgaris, Artemisia ulgarte Randodika (Artemisia oelandica), Artemisia Purinshipusu-Pump (Artemisia princeps Pamp), Artemisia Sakuraumu (Artemisia sacrorum), Artemisia scoparia (Artemisia scoparia), Artemisia Suterariana (Artemisia stelleriana), Artemisia Furijida-Wirudo (Artemisia frigida Willd ), Artemisia anethoides Matf., Artemisia anthefolia Weber., Artemisia Foley Nakai (Artem) 2. The composition of claim 1, selected from isia faurier Nakai, origanum vulgare, siphonostia chinensis, or any combination thereof.   The composition of claim 2, wherein the one or more biopolymers are extracted from the Artemisia plant using water, methanol, ethanol, alcohol, a water mixed solvent, or combinations thereof.   Aloe gel powders are aloe arborescens, aloe barbadensis, aloe cremonophila, aloe ferrox, aloe saponaria 2. The composition of claim 1 comprising vera), Aloe vera var. chinensis or a combination thereof.   The composition of claim 2, wherein the at least one chromone composition comprises from about 0.01% to about 100% of one or more chromones.   The composition according to claim 2, wherein the at least one chromone is selected from aloesin, aloesinol, alloresin A, alloresin B, allelesin C, allelesin D, allelesin E, or any combination thereof.   The chromone composition comprises about 1% to about 4% aloesin, the composition is essentially free of antroquinone, and the aloe gel is isolated from a plant selected from Aloe barbadensis or Aloe vera and comprises at least one species The composition of claim 2, wherein the chromone is isolated from Aloe vera or Aloe ferox, or any combination thereof.   Sisandra is one of the most popular varieties, including Schiandra chinensis, Sisandra elongate, Sisandra glabra, Sisandra glaucensens, Sisandra glaciensens, Sisandra henry , Sisandra lancifolia, Sisandra neglecta, Sisandra nigra, Sisandra propinq a), Sisandra pubescens, Sisandra repunda, Sisandra rubriflora, Sisandra rubisurai, Sisandra rubisurai, Shisandra sphaerandra, Sisandra sphenanthera, Sisandra tomentella, Sisandra tuberculata, Sisandra vesta 2. The composition of claim 1, comprising Tita (Schisandra vestita), Sisandra viridis, Sisandra wilsoniana, or a combination thereof.   At least one lignan isolated from the sisandren extract is sisandrin, deoxyschizandrin, gamma-schizandrin, pseudo-gamma-schizandrin, (Wuweizusu B), Uweizisu C (Wuweizusu C), Isosizandrin (Presomisin), Eosizandrin (B), Zizandol A (Shizandol) , C, D E (Schisantherin A, B, C, D, E), Rubuschisanthelin, Sisanhenol acetate, Sisanhenol B, Sisanhenol, C, D, E , F, G, H, J, N, O, R, S, T, U (Gomisin A, B, C, D, E, F, G, H, J, N, O, R, S, T, U,), epigomisin O, angeloyl gomisin H, O, Q, T (Angeloylgomisin) H, O, Q, T, iglooylgomisin H, P, angeloisogomisin O ( Angeley The benzoyl-gomosin H, O, P, Q, (Benzoyl-gomisin H, O, P, Q,) benzoyl-isogomisin, or a combination thereof. Composition.   3. The composition of claim 2, wherein the at least one organic acid is isolated from the sisandola extract and comprises malic acid, citric acid, shikimic acid, or a combination thereof.   The plant extract consists of stems, stem barks, stems, stem bark, twigs, tubers, roots, root barks, shoots, seeds, rhizomes, flowers and other reproductive organs, leaves, other aerial parts, or combinations thereof The composition according to claim 1, derived from at least one plant part selected from the group.   The plant extract consists of stems, stem barks, stems, stem bark, twigs, tubers, roots, root barks, shoots, seeds, rhizomes, flowers and other reproductive organs, leaves, other aerial parts, or combinations thereof The composition according to claim 2, derived from at least one plant part selected from the group.   The composition of claim 1, wherein the composition further comprises at least one hepatoprotectant.   The composition of claim 2, wherein the composition further comprises at least one hepatoprotectant.   At least one hepatoprotective agent is milk thistle, turmeric, curcula, bupleurum, licorice, salvia, morus, hovenia, hovenia, Hardgwa (cudrania), lyceum, citrus, prunus, yellow mume, Korean laver (Korea gim), dandelion, grape (vitis), grape seed (grape seed) , Rubus, camellia, green tea, krill oil, yeast Soy bean plant powder or plant extract; isolated and concentrated silymarins, flavonoids, phospholipids, thios, pycnogenol, gelatin, soy lecithin, pancreatic enzyme; natural or synthetic N-acetyl-cysteine, taurine, riboflavin, niacin, pyridoxine, folic acid, carotene, vitamin A, vitamin B2, B6, B16, vitamin C, vitamin E, glutathione, branched chain amino acid, selenium, copper, zinc, manganese, coenzyme 20. The composition of claim 19, comprising Q10, L-arginine, L-glutamine, phosphatidylcholine, or a combination thereof.   At least one hepatoprotective agent is milk thistle, turmeric, curcula, bupleurum, licorice, salvia, morus, hovenia, hovenia, Hardgwa (cudrania), lyceum, citrus, prunus, yellow mume, Korean laver (Korea gim), dandelion, grape (vitis), grape seed (grape seed) , Rubus, camellia, green tea, krill oil, yeast Soy bean plant powder or plant extract; isolated and concentrated silymarins, flavonoids, phospholipids, thios, pycnogenol, gelatin, soy lecithin, pancreatic enzyme; natural or synthetic N-acetyl-cysteine, taurine, riboflavin, niacin, pyridoxine, folic acid, carotene, vitamin A, vitamin B2, B6, B16, vitamin C, vitamin E, glutathione, branched chain amino acids, selenium, copper, zinc, manganese, coenzyme 21. The composition of claim 20, comprising Q10, L-arginine, L-glutamine, phosphatidylcholine, or a combination thereof.   2. The composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable or nutraceutical acceptable carrier, diluent or excipient.   3. The composition of claim 2, wherein the composition further comprises a pharmaceutically acceptable or nutraceutical acceptable carrier, diluent or excipient.   The composition of claim 1, wherein the composition comprises from about 0.5 weight percent (wt%) to about 90 wt% of the active ingredient of the mixture of plant extracts.   The composition of claim 2, wherein the composition comprises from about 0.5 weight percent (wt%) to about 90 wt% of the active ingredient of the mixture of plant extracts.   26. The composition of claim 25, wherein the composition is formulated as a tablet, hard capsule, soft gel capsule, powder, granule, liquid, tincture, sachet, ready-to-drink liquid or troche.   27. The composition of claim 26, wherein the composition is formulated as a tablet, hard capsule, soft gel capsule, powder, granule, liquid, tincture, sachet, ready-to-drink liquid or troche.   The composition of claim 1, wherein the composition is administered at a dose of 0.01 to 500 mg / kg animal body weight.   The composition according to claim 2, wherein the composition is administered at a dose of 0.01 to 500 mg / kg animal body weight.   A pharmaceutical composition that maintains liver function in mammals, minimizes hepatocyte damage, promotes a healthy liver, protects the liver's antioxidant integrity, neutralizes toxins, Reduces the effects of free radicals that affect health, captures reactive oxygen species, reduces oxidative stress, prevents the production of toxic metabolites, improves liver detoxification capacity and / or function, and cleans the liver Restores the structure of the liver, protects hepatocytes from toxins in the liver, helps the blood flow and circulation of the liver, assists the liver function, strengthens the liver, sedates, calms the liver, normalizes the liver Relieve pain, expel harmful chemicals and organisms, assist the metabolic processes of the liver, relieve liver discomfort, relieve fatty liver, improve liver detoxification ability, liver enzymes Reduce, give natural oxidant, increase SOD, G Increase H, reduce hepatocyte peroxidation, reduce fatty acid accumulation, maintain a healthy anti-inflammatory process, improve liver immune function, promote hepatocyte regeneration, liver regeneration function To improve, stimulate bile release, promote healthy bile flow, rejuvenate the liver, protect the liver from overnutrition, overwork, overdrinking, aging, etc. A pharmaceutical composition comprising the composition according to claim 1 as an active ingredient.   A pharmaceutical composition that maintains liver function in mammals, minimizes hepatocyte damage, promotes a healthy liver, protects the liver's antioxidant integrity, neutralizes toxins, Reduces the effects of free radicals that affect health, captures reactive oxygen species, reduces oxidative stress, prevents the production of toxic metabolites, improves liver detoxification capacity and / or function, and cleans the liver Restores the structure of the liver, protects hepatocytes from toxins in the liver, helps the blood flow and circulation of the liver, assists the liver function, strengthens the liver, sedates, calms the liver, normalizes the liver Relieve pain, expel harmful chemicals and organisms, assist the metabolic processes of the liver, relieve liver discomfort, relieve fatty liver, improve liver detoxification ability, liver enzymes Reduce, give natural oxidant, increase SOD, G Increase H, reduce hepatocyte peroxidation, reduce fatty acid accumulation, maintain a healthy anti-inflammatory process, improve liver immune function, promote hepatocyte regeneration, liver regeneration function To improve, stimulate bile release, promote healthy bile flow, rejuvenate the liver, protect the liver from overnutrition, overwork, overdrinking, aging, etc. A pharmaceutical composition comprising the composition according to claim 2 as an active ingredient.   Liver disorder or liver disease is viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, alcoholic liver disease, fatty liver disease, steatosis, steatohepatitis, nonalcoholic fatty liver disease, drug-induced liver disease, cirrhosis , Fibrosis, liver failure, drug-induced liver failure, metabolic syndrome, hepatocellular carcinoma, cholangiocarcinoma, primary biliary cirrhosis, capillary bile duct, Gilbert's syndrome, jaundice, or other liver toxicity related symptoms 32. The pharmaceutical composition of claim 31, wherein the composition is, in particular, with acceptable toxicity to the patient or any other liver related indication, or any combination thereof.   Liver disorder or liver disease is viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, alcoholic liver disease, fatty liver disease, steatosis, steatohepatitis, nonalcoholic fatty liver disease, drug-induced liver disease, cirrhosis , Fibrosis, liver failure, drug-induced liver failure, metabolic syndrome, hepatocellular carcinoma, cholangiocarcinoma, primary biliary cirrhosis, capillary bile duct, Gilbert's syndrome, jaundice, or other liver toxicity related symptoms 33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is, optionally, with acceptable toxicity to the patient or any other liver related indication, or any combination thereof.   3. Maintaining mammalian liver function, minimizing hepatocyte damage, promoting healthy liver and protecting liver antioxidant integrity, comprising administering an effective amount of the composition of claim 1 Neutralize toxins, reduce the effects of free radicals that affect liver health, capture reactive oxygen species, reduce oxidative stress, prevent the production of toxic metabolites, Or improve function, wash liver, restore liver structure, protect hepatocytes from toxins in liver, help liver blood flow and circulation, assist liver function, strengthen liver, sedate Calm, normalize, relieve liver pain, expel harmful chemicals and organisms, assist the liver's metabolic processes, relieve liver discomfort, relieve fatty liver, Improves detoxification capacity, reduces liver enzymes, natural oxidation , Increase SOD, increase GSH, reduce hepatocyte peroxidation, reduce fatty acid accumulation, maintain a healthy anti-inflammatory process, improve liver immune function, regenerate hepatocytes To improve liver regeneration function, stimulate bile release, promote healthy bile flow, rejuvenate the liver, protect the liver from overnutrition, overwork, overdrinking, aging, etc. Method.   3. Administering an effective amount of the composition of claim 2 to maintain mammalian liver function, minimize hepatocyte damage, promote healthy liver and protect liver antioxidant integrity Neutralize toxins, reduce the effects of free radicals that affect liver health, capture reactive oxygen species, reduce oxidative stress, prevent the production of toxic metabolites, Or improve function, wash liver, restore liver structure, protect hepatocytes from toxins in liver, help liver blood flow and circulation, assist liver function, strengthen liver, sedate Calm, normalize, relieve liver pain, expel harmful chemicals and organisms, assist the liver's metabolic processes, relieve liver discomfort, relieve fatty liver, Improves detoxification capacity, reduces liver enzymes, natural oxidation , Increase SOD, increase GSH, reduce hepatocyte peroxidation, reduce fatty acid accumulation, maintain a healthy anti-inflammatory process, improve liver immune function, regenerate hepatocytes To improve liver regeneration function, stimulate bile release, promote healthy bile flow, rejuvenate the liver, protect the liver from overnutrition, overwork, overdrinking, aging, etc. Method.   Liver disorder or liver disease is viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, alcoholic liver disease, fatty liver disease, steatosis, steatohepatitis, nonalcoholic fatty liver disease, drug-induced liver disease, cirrhosis , Fibrosis, liver failure, drug-induced liver failure, metabolic syndrome, hepatocellular carcinoma, cholangiocarcinoma, primary biliary cirrhosis, capillary bile duct, Gilbert's syndrome, jaundice, or other liver toxicity related symptoms 36. The method of claim 35, wherein the method is, typically, with acceptable toxicity to the patient or any other liver related indication, or any combination thereof.   Liver disorder or liver disease is viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, alcoholic liver disease, fatty liver disease, steatosis, steatohepatitis, nonalcoholic fatty liver disease, drug-induced liver disease, cirrhosis , Fibrosis, liver failure, drug-induced liver failure, metabolic syndrome, hepatocellular carcinoma, cholangiocarcinoma, primary biliary cirrhosis, capillary bile duct, Gilbert's syndrome, jaundice, or other liver toxicity related symptoms 37. The method of claim 36, wherein the method is, in particular, with acceptable toxicity to the patient or any other liver related indication, or any combination thereof.

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